While the sensation of nausea is universal in the human experience, the brain activity underlying this perceptual state is not well understood. Nausea is typified by epigastric discomfort with the urge to vomit, and autonomic nervous system (ANS) outflow characterized by sympathetic dominance. Nausea is a particularly debilitating symptom for patients with Cyclic Vomiting Syndrome (CVS, ROME III definition). CVS patients suffer from episodes of extreme nausea and vomiting, alternating with relatively symptom-free periods. While the pathophysiology of CVS is poorly understood, sympathovagal dysfunction and altered brain physiology have been proposed to play a significant role. Our group has successfully introduced metrics derived from functional MRI (fMRI) measures of resting, or intrinsic, brain connectivity as objective neurobiological correlates of pain in chroni pain patients. Our goal is to extend our approach to better characterize a different aversive subjective sensation - nausea. Our recent studies in healthy adults using combined visually-induced vection with concurrent fMRI and autonomic monitoring has suggested that the brain circuitry underlying nausea includes areas known to process interoception, as well as limbic and higher prefrontal cortical brain regions. These regions demonstrate greater connectivity to visual motion processing regions during motion sickness. Our preliminary data also suggests that fMRI signal from prefrontal and limbic cortical brain regions subserving the cognitive and affective components of nausea is more correlated with autonomic modulation during motion sickness. Hence, we hypothesize that CVS patients, even during their inter-episodic state, will demonstrate increased resting brain connectivity between the same interoceptive, affective, and cognitive processing regions identified during motion sickness in healthy adults. Such enhanced connectivity may predispose these patients to be hyper-responsive to central emetic signaling. Our overall goal is to evaluate the brain circuitry supporting nausea by contrasting intrinsic brai connectivity in CVS patients with that of healthy adults, both at rest and during a motion sickness-induced nausea state. Our Aims will evaluate functional brain connectivity associated with motion sickness-induced nausea in healthy adults, and investigate altered resting brain connectivity in CVS and its relationship to sympathetic dominance. Once completed, our long-term goal is to use the characterization of brain circuitry underlying nausea and CVS to establish objective neuroimaging biomarkers, which can be used to sub-phenotype CVS and other chronic nausea patients, and to define outcome measures for longitudinal trials in the development of novel therapies. PUBLIC HEALTH RELEVANCE: The goals of this project are to examine the brain circuitry of nausea in both healthy adults and patients with Cyclic Vomiting Syndrome. We will relate this circuitry with activity in the autonomic nervous system. This study will apply state of the art functional magnetic resonance imaging techniques to better understand brain response to motion sickness, comparing our findings with those of patients with chronic nausea.